Our microbiome influences how our immune system functions. Our microbiome has changed as a result of living in highly hygienic industrialized countries. A major change in our microbiome is loss of exposure to helminths (parasitic worms). Prior to the 1940's, helminth colonization was nearly universal and there is strong evidence that this exposure helped to shape our genome. Loss of these previously ubiquitous members of our paleobiome, can have far ranging immunologic effect. Inflammatory bowel disease (IBD) currently afflicts more than one million Americans and many thousands of veterans. The incidence of IBD and other immune-mediated diseases increased dramatically after the 1940's in North America and Europe. These diseases are rare in less developed tropical countries. Veterans that served in Vietnam or were prisoners of war are at lower risk of developing IBD than are other veterans. Moreover, as countries develop economically the incidence of IBD and other immune-mediated diseases increase. Now, IBD is a globally emerging disorder. Although specific genes predispose to IBD, there is strong evidence that a change in environment concurrent with socioeconomic improvement confers risk for developing the disorder. We propose that a change from our historic paleobiome, i.e. the lack of helminth exposure, in developed countries is an important risk factor for developing IBD and other immune-mediated diseases. We and others have shown that colonization with helminths protects mice from immune-mediated colitis, encephalitis, diabetes, and airway disease. These are models of diseases that have emerged within highly industrialized countries. Understanding how helminth exposure decreases immune mediated diseases will guide development of targeted therapy to prevent or treat those diseases. Th17 cells control pro-inflammatory pathological responses, like that of IBD. Recently it has become clear that Th17 cells are heterogeneous. In addition to making IL17, highly pro-inflammatory Th17 cells make IFN?. Other Th17 cells with a regulatory phenotype express FoxP3 or make IL10. Immune mediated disease likely results from dysregulated Th17 plasticity. We discovered that mucosal IL17 production is inhibited by exposure to helminths and that this exposure decreases Th17IFN?+ and increases Th17IL10+ percentages in lamina propria and mesenteric lymph node cell populations. Moreover, we find that helminth exposure alters Treg plasticity and in the absence of T cell Stat6-signaling massively induces a novel Foxp3+IFN?+ population. Our hypothesis is that helminth exposure protects against colitis by altering Th17 and Treg heterogeneity/plasticity. This project will test this hypothesis with 3 specific aims. Our first aim will explore the mechanisms enabled by helminth exposure that alter Th17 plasticity. Our second aim will explore the mechanisms enabled by helminth exposure that augment Treg plasticity and the role of newly discovered musculin and TIGIT circuity in helminth-associated Treg function. Our third aim will explore how helminth-induced changes in Th circuitry increases intestinal epithelial cell resistance to targeted injury. Our research is unique in that we are exploring possible root causes for the emergence of autoimmune and immune-mediated inflammatory disease in modern civilizations. In addition, these studies will provide insight into how helminth-exposed individuals that live or served in less developed countries may respond to immunologic challenges. Furthermore, we are examining in vivo how intestinal organisms alter immune pathways to influence chronic inflammatory diseases like those that afflict veterans.